The objectives of this proposal are: a) to obtain a clearer understanding of the basic metabolic defects in the various clinical forms of acid alpha-glucosidase deficiency; b) to identify genetic heterogeneity within each of the clinical forms of the disease; c) to evaluate the ability of purified human enzyme from various sources to correct the metabolic defect in cultured cells derived from patients with acid alpha-glucosidase deficiency; d) to study the catalytic, immunologic, and physiochemical properties of an electrophoretic variant of the acid isozyme of alpha-glucosidase which appears to be deficient towards the natural substrate glycogen; e) to measure the enzyme activity in cells from homozygotes and heterozygotes for the variant isozyme of acid alpha-glucosidase; f) to measure the turnover (synthesis and degradation) of acid alpha-glucosidase activity in cultured skin fibroblasts from normal subjects, from patients with the adult form of acid alpha-glucosidase deficiency, and in fibroblasts with the genotype 2-2 of acid alpha-glucosidase.